Hippocampal CA2 modulates trace fear conditioning through circuit-specific control of CA1.

Forming associations between temporally separated events depends on pathways linking the CA1, the subiculum (SUB), and the entorhinal cortex. The degree to which this process requires the CA2, which shares extensive connectivity with these regions, remains unknown. Using trace fear conditioning (TFC), where mice learn to associate a tone and shock separated by a temporal gap, we showed that the dCA2 contributes to TFC. Interestingly, whereas chronic dCA2 inhibition decreased cue-associated freezing, acute dCA2→dCA1 projection inhibition increased freezing. Combined with differential effects on cFos expression, this suggests that global and projection-specific perturbations of the dCA2 have distinct effects on TFC and hippocampal activity states. Fiber photometry revealed that dCA2→dCA1 activity shifted from tone responsiveness during conditioning to expected shock activation during recall, consistent with learning-associated activity remodeling. Together, these findings identify the dCA2 as a contributor to TFC and implicate dCA2→dCA1 signaling in shaping fear expression across learning and recall.